Naltrexone, an opioid antagonist, is currently used in oral tablet form to help maintain opioid addicts in a drug-free state. Most recently, naltrexone has been indicated as an adjunct in the treatment of alcohol dependence, as well as reported to reduce alcohol craving in certain alcoholic populations. Transdermal delivery of naltrexone is desirable for opioid addicts and alcoholics in order to help reduce side effects associated with oral therapy and improve compliance. Naltrexone itself does not have the essential physicochemical properties that would allow a therapeutic dose of the drug to cross the human skin barrier. We plan to continue designing and synthesizing derivatives (prodrugs), which are more skin permeable than naltrexone, in order to make a therapeutically successful drug delivery system. We hypothesize that prodrugs of naltrexone will improve the transdermal delivery rate of naltrexone, and that these prodrugs will make excellent research tools for investigating quantitative structure- permeability relationships (QSPRs) for transdermal flux and concurrent metabolism. These prodrugs should improve naltrexone delivery rates across the skin, because they are more lipophilic, less crystalline, and therefore more soluble than naltrexone.
The specific aims of this project include: (1) to synthesize a series of naltrexone prodrugs designed to elucidate fundamental QSPRs for transdermal flux and concurrent metabolism of the prodrugs, (2) to characterize the physicochemical parameters of the naltrexone prodrugs, including molecular weight, molecular volume, lipophilicity, hydrogen-bonding potentials, melting points, heats of fusion, and solubilities in select solvents, (3) to measure the naltrexone prodrugs' penetration and concurrent metabolism through human skin in vitro, (4) to characterize the pharmacokinetics of the naltrexone prodrugs in guinea pigs in vivo, and (5) to characterize the pharmacokinetics of the most promising naltrexone prodrugs in pigs in vivo. Correlation of our in vitro data with the in vivo models will aid in the creation of a reliable QSPR database, as well as help to identify the most promising prodrug for eventual human use.

Agency
National Institute of Health (NIH)
Institute
National Institute on Drug Abuse (NIDA)
Type
Research Project (R01)
Project #
1R01DA013425-01A2
Application #
6469406
Study Section
Human Development Research Subcommittee (NIDA)
Program Officer
Park, Moo Kwang
Project Start
2002-04-01
Project End
2005-03-31
Budget Start
2002-04-01
Budget End
2003-03-31
Support Year
1
Fiscal Year
2002
Total Cost
$253,400
Indirect Cost
Name
University of Kentucky
Department
Pharmacology
Type
Schools of Pharmacy
DUNS #
832127323
City
Lexington
State
KY
Country
United States
Zip Code
40506
Eldridge, Joshua A; Milewski, Mikolaj; Stinchcomb, Audra L et al. (2014) Synthesis and in vitro stability of amino acid prodrugs of 6-?-naltrexol for microneedle-enhanced transdermal delivery. Bioorg Med Chem Lett 24:5212-5
Ghosh, Priyanka; Lee, DoMin; Kim, Kyung Bo et al. (2014) Optimization of naltrexone diclofenac codrugs for sustained drug delivery across microneedle-treated skin. Pharm Res 31:148-59
Ghosh, Priyanka; Brogden, Nicole K; Stinchcomb, Audra L (2014) Fluvastatin as a micropore lifetime enhancer for sustained delivery across microneedle-treated skin. J Pharm Sci 103:652-60
Brogden, Nicole K; Banks, Stan L; Crofford, Leslie J et al. (2013) Diclofenac enables unprecedented week-long microneedle-enhanced delivery of a skin impermeable medication in humans. Pharm Res 30:1947-55
Ghosh, Priyanka; Brogden, Nicole K; Stinchcomb, Audra L (2013) Effect of formulation pH on transport of naltrexone species and pore closure in microneedle-enhanced transdermal drug delivery. Mol Pharm 10:2331-9
Ghosh, Priyanka; Pinninti, Raghotham R; Hammell, Dana C et al. (2013) Development of a codrug approach for sustained drug delivery across microneedle-treated skin. J Pharm Sci 102:1458-67
Milewski, Mikolaj; Paudel, Kalpana S; Brogden, Nicole K et al. (2013) Microneedle-assisted percutaneous delivery of naltrexone hydrochloride in yucatan minipig: in vitro-in vivo correlation. Mol Pharm 10:3745-57
Brogden, Nicole K; Ghosh, Priyanka; Hardi, Lucia et al. (2013) Development of in vivo impedance spectroscopy techniques for measurement of micropore formation following microneedle insertion. J Pharm Sci 102:1948-1956
Brogden, Nicole K; Milewski, Mikolaj; Ghosh, Priyanka et al. (2012) Diclofenac delays micropore closure following microneedle treatment in human subjects. J Control Release 163:220-9
Milewski, Mikolaj; Pinninti, Raghotham R; Stinchcomb, Audra L (2012) Naltrexone salt selection for enhanced transdermal permeation through microneedle-treated skin. J Pharm Sci 101:2777-86

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